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The Journal of Neuroscience, July 30, 2003, 23(17):6740-6747
 Previous Article | Next Article 
 -Amyloid Regulation of Presynaptic Nicotinic Receptors in Rat Hippocampus and Neocortex
John J. Dougherty,
Jianlin Wu, and
Robert A. Nichols
Department of Pharmacology and Physiology, Drexel University College of
Medicine, Philadelphia, Pennsylvania 19102
Alteration by  -amyloid (A) of signaling via nicotinic
acetylcholine receptors (nAChRs) has been implicated in the early stages of
Alzheimer's disease. nAChRs function both post- and presynaptically in the
nervous system; however, little is known about the functional consequence of
the interaction of A with these receptors, particularly those on
presynaptic nerve terminals. In view of the strong correlation between loss of
synaptic terminals and dementia, together with the reduction in nAChRs in
Alzheimer's disease, the possibility exists that presynaptic nAChRs may be
targets for A. To explore this possibility, we assessed the effect of
A peptides on nicotine-evoked changes in presynaptic Ca2+
level via confocal imaging of isolated presynaptic nerve endings from rat
hippocampus and neocortex. A1-42 appeared to inhibit
presynaptic nAChR activation by nicotine. Surprisingly, picomolar
A1-42 was found to directly evoke sustained increases in
presynaptic Ca2+ via nAChRs, revealing that the apparent inhibitory
action of A1-42 was the result of an occlusion of nicotine to
further stimulate the receptors. The direct effect of A was found to be
sensitive to  -bungarotoxin, mecamylamine, and
dihydro--erythroidine, indicating involvement of 7-containing
nAChRs and non-7-containing nAChRs. Prior depolarization strongly
attenuated subsequent A-evoked responses in a manner dependent on the
amplitude of the initial presynaptic Ca2+ increase, suggesting that
nerve activity or Ca2+ channel density may control the impact of
A on presynaptic nerve terminal function. Together, these results
suggest that the sustained increases in presynaptic Ca2+ evoked by
A may underlie disruptions in neuronal signaling via nAChRs in the early
stages of Alzheimer's disease.
Key words: nicotinic receptor; amyloid; presynaptic; hippocampus; calcium imaging; Alzheimer's disease
Received Feb. 13, 2003;
revised May. 27, 2003;
accepted May. 30, 2003.
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